DESCRIPTION (provided by applicant: It is clear that sex differences are a critical consideration to understanding the pathophysiology of mood disorders. While it is hypothesized as likely that susceptibility genes and hormones interact to modify the development of mood disorders, there exists limited current experimental evidence to support this. Numerous recent human genetic studies indicate a robust association between polymorphisms in CACNA1C, a gene that codes for the 11 subunit of the CaV1.2 L-type calcium channel, and a diagnosis of bipolar disorder or depression. We have recently identified sex differences in both humans and mice, which collectively indicate that CACNA1C genotype influences resilience to mood-related behavioral changes primarily in females, but the factors underlying these sex differences are unknown. The objective of this application is to use our mouse model to further assess the interaction between sex and Cacna1c genotype leading to the development of depression-related behavior, and to define the hormonal mechanisms that determine female-specific behavioral effects in Cacna1c haploinsufficient mice. Sex differences in the adult brain can be established early in development as a result of an organizational process mediated by gonadal hormones. The same gonadal hormones act on the adult brain and their actions may be constrained by earlier organizational processes or may, on their own, mediate sex differences in physiology and behavior. Our central hypothesis is that gonadal hormones interact with Cacna1c genotype during the early neonatal organizational period to modulate depression-related behavior at adulthood, and that decreased expression of Cacna1c will result in female mice that are resilient to the effects of chronic stress. Our specific aims are to: 1) Identify the role of activational effects of gonadal hormones in determining female-specific learned helplessness behavior in Cacna1c haploinsufficiency, 2) Identify the role of organizational effects of gonadal hormones in determining female-specific learned helplessness behavior in Cacna1c haploinsufficiency, and 3) Define the interaction between Cacna1c haploinsufficiency and sex in modifying behavior and brain plasticity in the chronic unpredictable stress model of depression. Our studies will improve understanding of the role of the Cacna1c gene in regulating behavior and other brain functions in a context relevant to the pathophysiology of mood disorders. Completion of the experiments describe in this application will provide critical support for the hypothesis that gonadal hormones and genetic risk factors interact at sensitive developmental time periods to modulate the risk to develop a mood disorder. Public Health Relevance: Once we complete these experiments it will then be possible to translate our findings to additional animal models and ultimately to humans, elucidating mechanisms and possible drug targets, and developmental time points for intervention in patients who suffer from mood disorders and who may carry CACNA1C risk alleles. PUBLIC HEALTH RELEVANCE: Recent human genetic studies indicate a robust association between polymorphisms in CACNA1C, a gene that codes for the 11 subunit of the CaV1.2 L-type calcium channel, and a diagnosis of bipolar disorder or depression. We have recently identified sex differences in both humans and mice, which collectively indicate that CACNA1C genotype influences mood-related behavioral changes primarily in females, but the factors underlying these sex differences are unknown. Completion of the experiments described in this application will provide critical support for the hypothesis that gonadal hormones and genetic risk factors interact at sensitive developmental time periods to modulate the risk to develop a mood disorder.